Adiponectin, a peptide hormone mainly produced by adipocytes, is now widely recognized as an insulin sensitizer that possesses anti-diabetic, anti-inflammatory and cardioprotective properties. However, the molecular mechanisms by which adiponectin signal is transduced and regulated in cells remains largely unknown. Our recent studies have demonstrated that APPL1 and its isoform APPL2 function as an integrated Yin- Yang regulator in adiponectin and insulin signaling (Mao et al., 2006, Nature Cell Biology, 8, 516-523) (Wang et al., 2009, J. Biol. Chem. 284, 31608-31615). However, the underlying mechanism and the in vivo roles of these isoforms in adiponectin and insulin action remain largely unknown. In current study, we have identified an APPL2 interactive protein, TCTP. We have demonstrated that TCTP interacts with both APPL1 and APPL2 in cells and that the interaction is regulated by adiponectin. In addition, we have found that altering the expression levels of TCTP significantly affects adiponectin signaling in mouse hepatocytes. Taken together, our overall hypothesis is that APPL2 is a negative regulator of adiponectin and insulin action in vivo and the interaction with TCTP may provide a mechanism by which APPL1-APPL2 Yin-Yang regulator coordinately controls adiponectin and insulin sensitivity in vivo. We will test this hypothesis by using in vitro and in vivo approaches as well as unique animal models in which the expression of APPL2 or TCTP is tissue-specifically altered. Our proposed studies should provide molecular mechanism underlying the regulation of insulin sensitivity, which will lead to identification of novel drug targets for new therapeutic strategies to prevent insulin resistance and diabetic complications.